Folate cofactors are essential for life. Mammals derive folates from their diet, whereas most microorganisms must synthesize folates de novo. Therefore, the folate pathway is an ideal target for developing anti-bacterial agents. For example, inhibitors of two enzymes in the pathway, dihydropteroate synthase and dihydrofolate reductase, are currently used as antibiotics. 6-Hydroxymethyl-7,8-dihydropterin pyrophosphokinase (E.C. 2.7.6.3, HPPK), a kinase responsible for an essential step in the biosynthesis of folic acid, catalyzes the transfer of pyrophosphate from ATP to 6-hydroxymethyl-7,8-dihydropterin (HP) (FIG. 1) (Shiota, T., 1984, in Chemistry and Biochemistry of Folates, R. T. Blakley, and S. J. Benkovic, eds. pp. 121-134, New York: John Wiley & Sons). No existing antibiotic is known to modulate HPPK activity. Due to in-depth structural and mechanistic studies of HPPK, this enzyme is well understood and therefore a good target for novel anti-bacterial compounds.
Two types of HPPK inhibitors (FIG. 1) have been reported (Derrick, J. P. (2008) The structure and mechanism of 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase, in G. Litwack, ed. Folic Acid and Folates, (Oxford, UK: Academic Press). Type 1 inhibitors are HP derivatives, including HP-1 (Hennig, M. et al., J. Mol. Biol. (1999) 287: 211-219; Wood, H. C. S. (1975) Specific inhibition of dihydrofolate biosynthesis—A new approach to chemotherapy, in Chemistry and Biology of Pteridines, W. Pfleiderer, ed. (Berlin-New York: Walter de Gruyter)) and HP-3. Type 2 inhibitors are bisubstrate analogues HPnA (n=2, 3, or 4) (Shi, G. et al., J. of Med. Chem. (2001) 44: 1364-1371). No pharmaceutically useful HPPK inhibitors have been identified to date. Thus, there remains a need for novel and useful HPPK inhibitor anti-bacterial compounds. The present disclosure fulfills this need and provides further advantages, which are set forth below.